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PHARMACOLOGY - Pulmonary > Note on Drugs for Lung Cancer > Flashcards

Note on Drugs for Lung Cancer Flashcards

1
Q

What type of Lung cancer are EGFR mutations typically associated with?

A

Adenocarcinomas

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2
Q

What EGFR monoclonals are used to treat lung cancer?
• what type of lung cancer are they used to treat?
• MOA?

A

Necitumumab Panitumumab

• Indicated in SQUAMOUS NSCLC

MOA: Competitively block binding of EFT and TGF-alpha to EGFR inhibiting receptor autophosphorylation

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3
Q

How is activity of Tyrosine Kinase Inhibitors, specifically EGFR, Blocked?

A
  • Binding Site Mutation
  • Increased activity of MET (phosphorylating enzyme)
  • Binding of HGF to HGFR to kick of the PI3K/Akt path
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4
Q

When TK inhibitors loose their efficacy in a patient, what mutations (2) are likely to have occured?
• How do these mutations differ in their ability to make TKIs less effective?

A

Mutations that change cell sensitivity to TK singaling:
• Exon 19 (in-fram deletion)
• Point mutation in exon 21 (L858R)

Mutations (or natural varients) with Mutated ATP binding site:
• T790M
**Note: T790M may naturally occur**

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5
Q

What downstream mutations may be used to render anti-EGFR (mAbs or PKIs) drugs useless?

A

Mutatations in any downstream enzyme can render the drug ineffective

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6
Q

Why is it bad when genes fuse to yeild fusion proteins with ALK?
• What is the primary mutation involving the ALK gene that leads to NSCLC?
• what pathway is kicked off?

A

Mutations involving the formation of ALK fusion proteins leads to the formation of constitutively activated Tyrosine Kinases
• EML4-ALK is the most common (seen in non-smokers, light smoking history, and pts. with adenocarcinomas)
• MEK/ERK, PI3K, JAK-STAT path is activated

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7
Q

What is the relationship between VEGF, VHL, and HIF-1alpha?

A

VHL lets off of hypoxia inducible factor -1 (HIF-1) in hypoxic conditions typically so that HIF-1 can induce the transciption of growth factors including VEGF to reduce hypoxia

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8
Q

What are the down sides to using and anti-VEGF drug?

A
  1. Reduction in vasculature may reduce the distribution of concurrent chemotherapy
  2. Selection for the most aggressive cells may occur
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9
Q

What are some mutations that are seen more often in NSCLC in non-smokers than smokers?
• What is the most common in smokers?

A

Most common mutation in smokers:
• KRAS (30-40%)

Mutations more common among non-smokers:
• EGFR mutations
• EML4-ALK fusion
• HER2-mutations

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10
Q

What lung cancer patients should undergo testing for EGFR and ALK rearrangments?

A

ALL adenocarcinomas should undergo testing for EGFR or ALK mutations (squamous cell carcinoma testing is not currently recommended)

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11
Q

Why is Chemotherapy the only option in SCLC?

A

Metathesis occurs very early on so Chemotherapy and Radiation are the only good options

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12
Q

What are the conventional drugs used to treat SCLC?

A

Etoposide and Cisplatin or Carboplatin or…

Cisplatin + irinotecan
Cisplatin + etoposide + ifosfamide
Cyclophosphamide + doxorubicin and/or etoposide ± vincristine

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13
Q

What are the conventional treatment options for NSCLC?
• what is maintenance therapy for these pts?

A

CISPLATIN and Taxane (Paclitaxel, Docetaxel), Vinca alkaloid (vinorelbine), Gemcitabine (Ribonuc. reducase and DNA pols. inhibit), Irinotecan (topoisomerase inhibitor) or Pemtrexed (DHFR inhibitor - methotrexate analogue)

Maintainance via Pemtrexed

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14
Q

What lung cancer patients can you give EGFR TKIs to?

A

NSCLC Patients with EGFR positive genetic test

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15
Q

What lung cancer patients can get Bevacizumab?

A

Bevacizumab - NSCLC patients with non-squamous histology, no brain metastatses, or hemoptysis

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16
Q

T or F: Toxicities of newer targeted drugs affect nearly every organ system in the body.

A

True, **The majority of these drugs are administered in a continuous fashion making cumulative toxicities a COMMON event**

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17
Q

How do we minimize the toxicity of targeted drugs?

A

Surveillance and Early Management are key to minimizing treatment interruption

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18
Q

Afatinib
• Target

A

Target:
• EGFR, exon 19 del or 21 subs

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19
Q

Alectinib
• Target

A

Target
ALK

20
Q

Ceritinib
• Target
• Indication?

A

Target:
ALK

Indication:
Patients that are intolerant to crizotinib

21
Q

Crizotinib
• Target?

A

Target
• ALK, and HGFR

22
Q

Eroltinib
• Target

A

Target:
EGFR, exon 19 del or 21 subs

23
Q

Gefitinib
• Target

A

Target:
EGFR, exon 19 del or 21 sub

24
Q

Osimertinib
• Target

A

Target:
EGFR, 790M mutation positive

25
Q

What KEY toxicity is seen in patients receiving EGFR targeting drugs (mAb or TKI)?
• Who typically experiences this effect?
• Who doesn’t?

A

SEVERE RASH - makes sense b/c you’re inhibiting Epithelial Growth Factor

  • YOUNGER MALE patients are more likely to get this rash
  • Patient who smoke and have light skin pigmentation are more immune
26
Q

What KEY toxicity is seen in targeted therapies towards angiogenesis?

A

HYPERTENSION (20%)***, Hemorrhage, Thrombosis, CARDIAC CONTRACTILE DYSFUNCTION- makes sense given that these are preventing new vessels from being formed

Damage to Matrix is not repaired as well without VEGF and we see exposure of the underlying matrix leading to Thrombosis and Hemorrhage

27
Q

In patients using targeted therapies, especially TKIs, what should you advise them to do or not do?

A

Avoid Pregnancy - make sure they’re using contraception

Avoid Breastfeeding - concerns over neonatal drug toxicity

Tell them to report and Dematologic, Cardiac, or Pulmonary symptoms since these are common

28
Q

Which tyrosine kinase inhibitors used in lung cancer target EGFR exon 19 del or 21 subs?
• 790M mutations (exon 20)?

A

Exon 19 del or 21 subs:
Afatinib
Eroltinib
Gefitinib

790M mutations:
Osimertinib

29
Q

What Tyrosine Kinase Inhibitors used in lung cancer target ALK?
• differentiate between these on the basis of other targets.

A

ALK TKIs:
• Alectinib
• Ceritinib (ppl. intolerant to crizotinib)
• Crizotinib (also targets HGFR)

30
Q

What are some things you should consider by the fact that TKIs are taken orally?

A
31
Q

Some physicians use the rash induced by TKIs as an indicator that the drug is working. What should you do to ensure that the drug is staying at a constant level in their bloodstream?

A

To ensure consistent plasma levels advise against taking these drugs with Food or Grapefruit Juice

32
Q

Bevacizumab
MOA
Adverse Effects
Contraindications

A

MOA
mAb that binds VEGF receptor and prevents activation

Adverse Effects
Hand-Foot syndrome, HTN, hemmorhage, cardiac dysfuncton, Thormbosis, Fistula formation

Contraindications
High Risk for Hemorrhage:
• NSCLC (especially those with squamous histology), renal cell carcinoma, colorectal cancer - causes central tumor necrosis leading to hemorrhage

33
Q

Ramucirumab
MOA
Contraindications

A

MOA
Inhibits VEGF2 receptor

Adverse Effects
Neutropenia, HTN, Hemorrhage (monitor BP)

Contraindications
Unlike Bevicizumab, Ramucirumab is NOT contraindicated with Squamous Carcinoma NSCLC

34
Q

Why do patients with functional p53 probably not respond to VEGF inhibitors as dramatically as those with a p53 mutation?

A
  • VHL binds HIF-1alpha under normal circumstance but lets it go under hypoxic circumstances
  • If hypoxia is induced then HIF-1 alpha will go ot the nucleus and transcribe VEGF HOWEVER…
  • In prolonged Hypoxia p53 represses HIF-1 alpha
35
Q

What is the idea behind PD-1 antibodies used in cancer treatment?

A

PD-1 is a receptor found on Tcells that downregulates their activity when bound to their ligand PD-1L. Many cancers upregulate PD-1L to avoid T cell recognition as foreign. Inhibiting this system is beneficial to allowing T cells “see” the cancer.

36
Q

What mAb drugs work by inhibiting PD-1 receptors?
• what is the advantage to these drugs?
• what major risk is associated with taking these drugs?

A

Nivolumab
Pembrolizumab

*compared to TKIs, these mAbs have pretty mild effects

Major Risks:
• May induce AUTOIMMUNE disease (like pneumonitis, hypo/hyperthyroidism)

37
Q

What happens when the phosphorylation step to EGFR is blocked?

A

Cell undergoes apoptosis

**Even with this resistance mechanisms like the binding of MET (aka HGFR) can come in a phosphorylate EGFR, or HGF can just kick off the pathway itself**

38
Q

Carboplatin and Cisplatin
MOA
Toxicity
Remedy

A

MOA
Form DNA intrastrand crosslinks and adducts

Toxicity:
Carboplatin less toxic than cisplatin
• Nephro- and ototoxicity
• Peripheral Neuropathy

Remedy
• Amifostine is nephro-protective
• Prophylax for SEVERE N/V

**Dose Limiting Toxicity in Cisplatin = nephro and ototoxicity***

39
Q

Cyclophosphamide, Ifosphamide
MOA
Toxicity

A

MOA:
Pro-drug of active alkylating moiety

Toxicity:
BMS, HEMORRHAGIC CYSTITIS from ACROLEIN

•Mesna = renoprotective

40
Q

Docetaxel, Paclitaxel
MOA
Toxicity

A

MOA:
• Microtubule Stabilizer inhibiting depolymerization

Toxicity:
• Mucositis, Peripheral neuropathy, Hypersensivity

41
Q

Doxorubicin
MOA
Toxicity
Protection

A

MOA
Intercalator, free radical generator, topo II inhibitor

Toxicity:
Red-Orange Urine, Acute cardiac arrythmia, Chronic cardiomyopathy (CHF)

Dexrazoxan = protective chelator

**Cumulative-Dose cardiotoxicity = Dose limiting**

42
Q

Etoposide, VP-16
MOA
Toxicity

A

MOA:
• DNA-topo II complex stabilizer

Toxicity:
BMS, N/V, HYPOTENSION, hypersensitivity

43
Q

Gemcitabine
MOA
Toxicity

A

MOA
DNA pols inhibitor via incorporation of triphosphate form during DNA systhesis

Toxicity
INTERSTITIAL PNEUMONITIS, Peripheral Neuropathy, BMS, mucositis, etc.

44
Q

Irinotocan and Topotecan
MOA
Toxicity

A

MOA
DNA-topo I complex stabilizer

Toxicity:
ASTHENIA, BMS, N/V

45
Q

Vincristine and Vinorelbine

MOA
Toxicity

A

MOA
Microtubule inhibitor; tubules disintegrate into spiral aggregates/protofilaments

Toxicity
VINCRISTINE - SIADH!!!
Peripheral neuropathy (less so with vinorelbine)

PHARMACOLOGY - Pulmonary (30 decks)

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